We propose one placebo-controlled, double-blind, outpatient clinical study to examine the efficacy of a 5-HT3 antagonist, ondansetron, and its interaction with several biological and psychosocial factors influencing alcoholism treatment outcome. Ondansetron has been shown to reduce preference and consumption of alcohol in a variety of animal models. Our human laboratory experiments also have shown that ondansetron attenuates some alcohol-induced subjective effects including the desire to drink. In a preliminary clinical trial, ondansetron reduced alcohol consumption by up to 30%. However, the findings of this clinical study were limited because of an inadequate sample size, medication was provided without any psychologically based counseling, there were no female subjects, and follow-up was insufficient. Ondansetron has considerable potential as a therapeutic agent for treating alcoholism. Our principal goal is to evaluate the efficacy of ondansetron in the treatment of alcohol dependent patients receiving standardized cognitive-behavioral coping skills therapy in a double-blind, placebo-controlled clinical trial. Research has suggested that there are two types of alcoholism. Individuals with early onset alcoholism (EOA) characterized by early onset of alcohol related problems, childhood familial vulnerability, greater severity of illness, polydrug abuse, and possibly, increased likelihood of serotonin abnormality. In contrast, individuals with late onset alcoholism (LOA) have a later onset of problem drinking, and a more benign course of illness and outcome. This study will prospectively "type" subjects into EOA or LOA groups to determine whether these alcoholism types differ on treatment outcome. A variety of psychosocial measures will be used retrospectively to examine the validity of this classification scheme. 400 male and female alcoholics who are currently drinking will be assigned to one of eight treatment groups in a 4 x 2 factorial design comparing the EOA groups (placebo, 3.5, 14 and 56 micrograms/Kg b.i.d.) with the LOA groups (placebo, 3.5, 14 and 56 micrograms/Kg b.i.d). EOA and LOA groups will be of similar age and sex distribution. For 12 weeks, all patients will receive daily medication and weekly cognitive-behavioral coping skills therapy using the NIAAA manual. Alcohol consumption will be measured by self-report and alcohol meter readings, and corroborated by serum levels of the carbohydrate deficient transferrin enzyme (CDT) and gamma glutamyl transferase (GGT). The sensitivity of CDT and GGT to changes in alcohol consumption will also be compared. Also, measures of alcohol craving, motivation to change, self-efficacy, decisional balance, social functioning, and changes in mood will be taken weekly. Biochemical tests will determine whether the EOA and LOA groups show differences in serotonergic function or whether individual differences in these variables predict treatment outcome. Clinical outcome will be re-evaluated at 1, 2, 3, 6, 9, and 12 months follow-up post-treatment. This study supports NIAAA's goal to develop effective medications to treat alcoholism.